Platelet-activating factor plays a pivotal role in the induction of experimental lung injury.
We have previously described a model of acute lung injury in the mouse in which intravenous administration of lipopolysaccharide (LPS) results in a marked sequestration of neutrophils in the pulmonary microvasculature, although this by itself was not sufficient to induce injury. If the sequestered neutrophils were exposed to zymosan, then a striking increase in pulmonary vascular permeability to albumin was found, suggesting that sequestered neutrophils may produce one or more mediators capable of acting directly on the capillary endothelium. Because activated neutrophils are known to release platelet-activating factor (PAF), we hypothesized that PAF produced locally within the pulmonary capillaries may be the mediator involved. Treatment of mice with the PAF antagonist UK-74,505 prior to administration of zymosan alone or combined LPS and zymosan resulted in a substantial attenuation of lung injury, as measured by the accumulation of extravascular 125I-labeled human serum albumin. UK-74,505 had no effect on neutrophil sequestration as measured by myeloperoxidase activity in whole lung tissue and as assessed by light microscopy. Administration of UK-74,505 after LPS, but before zymosan, was also effective at inhibiting lung injury but again, neutrophil sequestration was unaffected. In contrast, UK-74,505 had no effect on cobra venom factor-induced lung injury and neutrophil sequestration. These data suggest that PAF production is involved in the increases in pulmonary vascular permeability, but not in the sequestration of neutrophils, induced by zymosan alone or by combined LPS and zymosan treatment. Early treatment with PAF antagonists may be beneficial in preventing the development of acute lung injury in humans.
Miotla
J M
JM
Applied Pharmacology and Lung Pathology, Imperial College School of Medicine at the National Heart and Lung Institute, London, United Kingdom.
Jeffery
P K
PK
Hellewell
P G
PG
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D004095:Dihydropyridines / Q000494:pharmacology*; D004195:Disease Models, Animal; D004546:Elapid Venoms / Q000494:pharmacology; D015633:Extravascular Lung Water; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008168:Lung / Q000276:immunology / Q000503:physiopathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000201:enzymology; D009195:Peroxidase / Q000378:metabolism; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D010980:Platelet Membrane Glycoproteins / Q000502:physiology; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000276:immunology / Q000503:physiopathology*; D012709:Serum Albumin / Q000032:analysis; D012867:Skin; D015054:Zymosan / Q000008:administration & dosage
D004095:Dihydropyridines; D004546:Elapid Venoms; D007093:Imidazoles; D008070:Lipopolysaccharides; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D012709:Serum Albumin; C016310:cobra venom factor; C039351:platelet activating factor receptor; C073027:modipafant; D015054:Zymosan; D009195:Peroxidase